One of the most fundamental problems in molecular biology is understanding the molecular origin of enzyme catalysis. We propose here a continuation of our project aimed at resolving the secret of enzyme catalysis by finding quantitative correlations between the structures of enzyme-substrate complexes and the activation free energies of the corresponding enzymatic reactions. In recent years we developed theoretical methods that enable us to calculate the activation energies of enzymatic reactions and the corresponding reactions in solution. These approaches have indicated that the transition states of enzymatic reactions possess very significant ionic character and that the electrostatic interactions of the enzyme dipoles with such transition states might be the most important factor in enzyme catalysis. In the proposed project we intend to continue in our studies, concentrating on two main directions: 1) Refinement and examination of our calculation method. 2) Extensive examination of the role of electrostatic interactions in enzyme catalysis and other biological processes. This study will involve a large scale comparative analysis of the reactivity of many enzymes with particular attention to the origin of the differences in reactivity between related enzymes (e.g. trypsin and trypsinogen). Other proposed topics include: 1) calculations of pKa's in proteins. 2) calculations of the relation between the structure of cytochromes and their redox potentials. 3) study of the role of electrostatic interactions in allosteric systems (e.g. hemoglobin). 4) calculations of the energetics of salt bridges. 5) calculations of the effect of protein electrostatic potentials on the spectroscopic properties of their chromophores and 6) extensive studies of chemical reactions in solutions.